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Objective: Chronic low-grade inflammation of the pancreatic islets is the characteristic of type 2 diabetes (T2D), and some of the immune checkpoints may play important roles in the pancreatic islet inflammation. Thus, we aim to explore the immune checkpoint genes (ICGs) associated with T2D, thereby revealing the role of ICGs in the pathogenesis of T2D based on bioinformatic analyses. Methods: Differentially expressed genes (DEGs) and immune checkpoint genes (ICGs) of islets between T2D and control group were screened from datasets of the Gene Expression Omnibus (GEO). A risk model was built based on the coefficients of ICGs calculated by ridge regression. Functional enrichment analysis and immune cell infiltration estimation were conducted. Correlations between ICGs and hub genes, T2D-related disease genes, insulin secretion genes, and beta cell function-related genes were analyzed. Finally, we conducted RT-PCR to verify the expression of these ICGs. Results: In total, pancreatic islets from 19 cases of T2D and 84 healthy subjects were included. We identified 458 DEGs. Six significantly upregulated ICGs (CD44, CD47, HAVCR2, SIRPA, TNFSF9, and VTCN1) in T2D were screened out. These ICGs were significantly correlated with several hub genes and T2D-related genes; furthermore, they were correlated with insulin secretion and ß cell function-related genes. The analysis of immune infiltration showed that the concentrations of eosinophils, T cells CD4 naive, and T cells regulatory (Tregs) were significantly higher, but CD4 memory resting T cells and monocytes were lower in islets of T2D patients. The infiltrated immune cells in T2D pancreatic islet were associated with these six ICGs. Finally, the expression levels of four ICGs were confirmed by RT-PCR, and three ICGs were validated in another independent dataset. Conclusion: In conclusion, the identified ICGs may play an important role in T2D. Identification of these differential genes may provide new clues for the diagnosis and treatment of T2D.
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OBJECTIVES: This study aims to investigate the use of high-frequency sonography as a tool for detecting inflammatory and destructive changes in the hand and foot joints of patients with early and long-term RA. METHODS: This study employs a prospective cohort design involving 162 patients diagnosed with Rheumatoid arthritis (RA) who meet the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria. Patients were divided into two groups based on disease duration: Group 1 (n = 74) included patients with a disease duration of up to 2 years, or early Ð Ð (ERA;), Group 2 (n = 88) consisted of patients with a disease duration exceeding 2 years, or long-term persistent Ð Ð (LtRA). All patients underwent a clinical assessment of their joints, as well as radiography and arthrosonography, at the beginning of the study and again at 6 and 12 months later. RESULTS: In the general group of patients, ultrasound examination revealed signs of synovitis in the joints of the hands more frequently (66%) compared with clinical examination (56% by a number of swollen joints [NSJ] and 55% by a number of painful joints [NPJ], P < .01). After 6 months of treatment, 12% of the patients achieved full US remission and 24% achieved partial US remission. CONCLUSIONS: Within the scope of comprehensive RA diagnostics, arthrosonography of the joints of the hands and feet, utilizing a combination of greyscale and power Doppler, may surpass radiography in detecting early RA. This method allows for a more accurate assessment of disease activity and progression rates.
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Artritis Reumatoide , Progresión de la Enfermedad , Ultrasonografía , Humanos , Artritis Reumatoide/diagnóstico por imagen , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ultrasonografía/métodos , Estudios de Cohortes , Adulto , Anciano , Reproducibilidad de los Resultados , Articulaciones de la Mano/diagnóstico por imagenRESUMEN
In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients' prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients' survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.
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Regulación Neoplásica de la Expresión Génica , Neoplasias , Medicina de Precisión , Transcriptoma , Humanos , Transcriptoma/genética , Neoplasias/genética , Neoplasias/clasificación , Neoplasias/patología , Pronóstico , Perfilación de la Expresión Génica , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/clasificación , Carcinoma Hepatocelular/patología , Mutación/genética , Microambiente Tumoral/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/patología , Oncología Médica/métodosRESUMEN
SCOPE: Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes vascular damage in renal interlobar arteries (RIA) from offspring still keeps unclear. METHODS AND RESULTS: Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Swollen mitochondria and distributed myofilaments are observed in vascular smooth muscle cells of RIA exposed to prenatal HS. Maternal HS increases phenylephrine (PE)-induced vasoconstriction in the RIA from adult offspring. NG-Nitro-l-arginine (L-Name) causes obvious vascular tension in response to PE in offspring from control group, not in HS. RNA-Seq of RIA is performed to reveal that the gene retinoid X receptor g (RXRg) is significantly decreased in the HS group, which could affect vascular function via interacting with PPARγ pathway. By preincubation of RIA with apocynin (NADPH inhibitor) or capivasertib (Akt inhibitor), the results indicate that ROS and Akt are the vital important factors to affect the vascular function of RIA exposure to prenatal HS. CONCLUSION: Maternal HS during the pregnancy increases PE-mediated vasoconstriction of RIA from adult offspring, which is mainly related to the enhanced Akt and ROS regulated by the weakened PPARγ-RXRg.
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PPAR gamma , Efectos Tardíos de la Exposición Prenatal , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Transducción de Señal , Vasoconstricción , Animales , Embarazo , Femenino , PPAR gamma/metabolismo , PPAR gamma/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Sacarosa en la Dieta/efectos adversos , Ratas , Arteria Renal/efectos de los fármacos , Masculino , Fenilefrina/farmacología , Fenómenos Fisiologicos Nutricionales MaternosRESUMEN
Full-color luminophores have advanced applications in materials and engineering, but constructing color-tunable clusteroluminescence (CL) from nonconjugated polymers based on through-space interactions remains a huge challenge. Herein, we develop phosphine-capped nonconjugated polyesters exhibiting blue-to-red CL (400-700 nm) based on phosphine-initiated copolymerization of epoxides and cyclic anhydrides, especially P1-0.5TPP, which exhibits red CL (610 nm) with a high quantum yield of 32%. Experiments and theoretical calculations disclose that the phosphine-capped effect in polyesters brings about conformational changes and induces phosphine-ester clusters by through-space (n,π*) interactions. Moreover, CL colors and efficiencies can be easily tailored by types of phosphines, compositions and structures of polyesters, and concentration. Significantly, the role of polymer motions (group, segmental, and chain motions) on CL originating from microregions inside polyesters is revealed. Further, phosphine-capped nonconjugated polyesters are demonstrated to be nonconjugated dyes and fluorescent fibers and are also used for multicolor light-emitting diodes including white light. This work not only provides an engineering strategy based on the end-group effect to prepare full-color clusteroluminogens but also broadens the prospects for material applications.
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Organic radicals with narrow energy gaps are highly sought-after for the production of near-infrared (NIR) fluorophores. However, the current repertoire of developed organic radicals is notably limited, facing challenges related to stability and low fluorescence efficiency. This study addresses these limitations by achieving stable radicals in nonconjugated poly(diphenylmethane) (PDPM). Notably, PDPM exhibits a well-balanced structural flexibility and rigidity, resulting in a robust intra-/inter-chain through-space conjugation (TSC). The stable radicals within PDPM, coupled with strong TSC, yield a remarkable full-spectrum emission spanning from blue to NIR beyond 900â nm. This extensive tunability is achieved through careful adjustments of concentration and excitation wavelength. The findings highlight the efficacy of polymerization in stabilizing radicals and introduce a novel approach for developing nonconjugated NIR emitters based on triphenylmethane subunits.
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Assistive medical image classifiers can greatly reduce the workload of medical personnel. However, traditional machine learning methods require large amounts of well-labeled data and long learning times to solve medical image classification problems, which can lead to high training costs and poor applicability. To address this problem, a novel unsupervised breast cancer image classification model based on multiscale texture analysis and a dynamic learning strategy for mammograms is proposed in this paper. First, a gray-level cooccurrence matrix and Tamura coarseness are used to transfer images to multiscale texture feature vectors. Then, an unsupervised dynamic learning mechanism is used to classify these vectors. In the simulation experiments with a resolution of 40 pixels, the accuracy, precision, F1-score and AUC of the proposed method reach 91.500%, 92.780%, 91.370%, and 91.500%, respectively. The experimental results show that the proposed method can provide an effective reference for breast cancer diagnosis.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Aprendizaje Automático , Mamografía , Simulación por ComputadorRESUMEN
BACKGROUND: A healthy lifestyle is an important factor for preventing heart failure. However, the association between outdoor light exposure time and heart failure is still unknown. The aim of this study was to examine the association between outdoor light exposure time and the incidence of heart failure. METHODS AND RESULTS: This cohort study included participants from the UK Biobank recruited from 2006 to 2010 who were 40 to 70 years of age and free of heart failure at baseline. The mean follow-up time was 12.61 years. The outdoor light exposure time was self-reported at baseline. A restricted cubic spline was performed to examine the potential nonlinear relationship between outdoor light exposure and the incidence of heart failure. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% CIs. During a mean follow-up of 12.61 years, 13 789 participants were first diagnosed with heart failure. There was a nonlinear (J-shaped) trend between outdoor light time and heart failure risk. Cox proportional hazard regression models showed that, compared with participants who received an average of 1.0 to 2.5 hours of outdoor light per day, those with <1.0 hours or >2.5 hours had a higher risk of heart failure after the model was adjusted for age and sex (<1.0 hours: HR, 1.27 [95% CI, 1.18-1.36]; >2.5 hours: HR, 1.11 [95% CI, 1.07-1.15]). These associations were still significant in the fully adjusted models (<1.0 hours: HR, 1.10 [95% CI, 1.03-1.18]; >2.5 hours: HR, 1.07 [95% CI, 1.03-1.11]). CONCLUSIONS: We found a J-shaped association between outdoor light exposure time and the risk of incident heart failure, suggesting that moderate exposure to outdoor light may be a prevention strategy for heart failure.
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Insuficiencia Cardíaca , Humanos , Estudios de Cohortes , Autoinforme , Insuficiencia Cardíaca/epidemiología , Factores de RiesgoRESUMEN
Near-infrared luminophores have many advantages in advanced applications, especially for structures without π-conjugation aromatic rings. However, the fabrication of red clusteroluminogens from nonconjugated polymers is still a big challenge, let alone the near-infrared clusteroluminogens. Here, we develop nonconjugated luminophores with full-spectrum from blue to near-infrared light (470 ~ 780 nm), based on color phenomenon of nonconjugated polyesters synthesized from the amine-initiated copolymerization of epoxides and cyclic anhydrides. We reveal that amines act as initiators attached to polymer chain ends. The formation of various amine-ester complexes in polyesters induces red to near-infrared light, conceptually, amine-ester complexed clusteroluminescence via intra/inter-chain charge transfer. Significantly, emission colors can be easily tuned by the contents and types of amines, microstructures of polyesters, and their concentration. This work provides a low-cost, scalable platform and strategy for the production of high-efficiency, multicolor luminescent materials.
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The crystal plane effect has gained extensive attention in heterogeneous catalysis reactions; however, it is far from being systematically probed in titanium dioxide (TiO2)-supported vanadium catalysts. Herein, a series of vanadium (V) single atoms and clusters anchored on TiO2 with different crystal planes was fabricated by an improved "top-down" protocol. The dispersion state, electronic structure, and redox properties of the V single-atom and VOx cluster-supported catalysts were systematically analyzed by a series of characterization methods, including X-ray absorption near edge structure (XANES) and density functional theory (DFT) calculations, and their catalytic performances were examined for aerobic oxidative desulfurization (AODS) of 4,6-dimethyl-dibenzothiophen (4,6-DMDBT) with O2 as the oxidant. The results unveiled that the synergistic effect between the V single atom and the VOx cluster perceptibly promoted the catalytic performances of VOx/TiO2 samples. Therein, VOx/TiO2-(001) shows the lowest apparent activation energy (Ea) value of 46.3 kJ/mol and the optimal AODS performance with complete 4,6-DMDBT conversion to 4,6-dimethyldibenzothiophene sulfone (4,6-DMDBTO2) within 60 min at 120 °C as compared with VOx/TiO2-(101) (81.9 kJ/mol and 180 min) and VOx/TiO2-(100) (68.0 kJ/mol and 240 min), which should be attributed to its higher V5+/V4+ ratio, the optimal redox behavior of the V species, the moderate adsorption energy between 4,6-DMDBT and VOx active centers, and the synthetic effect of V single atoms and VOx clusters. Moreover, VOx/TiO2-(001) exhibits robust durability in seven cycles of reuse, showcasing the potential for practical applications in the future.
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Making nonconjugated polymers to emit visible light remains a formidable challenge, let alone near-infrared (NIR) light, although NIR luminophores have many advanced applications. Herein, we propose an electron-bridging strategy of using heteroatoms (O, N, and S) to achieve tunable emission from blue to NIR regions (440-800 nm) in nonconjugated polyesters. Especially, sulfur-containing polyester P4 exhibits NIR clusteroluminescence (CL) on changing either the concentration or excitation wavelength. Experimental characterization and theoretical calculation demonstrate that the introduction of heteroatoms significantly enhances the through-space interactions (TSIs) via the electron-bridging effect between heteroatoms and carbonyls. The strength of the electron-bridging effect follows the order of S > N > O, based on two synergistic effects: electronic structure and van der Waals radius of heteroatoms. This work provides a low-cost, scalable platform to produce new-generation nonconjugated luminophores with deeper insight into the photophysical mechanism.
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Over 16 million children have been detected positive for the coronavirus disease 2019 (COVID-19) in the United States since the outbreak of the pandemic. In general, children infected with severe acute respiratory syndrome coronavirus type 2 tend to have lighter symptoms than adults. However, in some cases, the infection can develop into severe forms, such as multisystem inflammatory syndrome in children. Moreover, long-term public health preventive interventions have had some negative effects on the physical and mental health of children. Given the important role that vaccination plays in reducing severe illness and mortality, it is essential for the efficient implementation of vaccination in the pediatric population. Nevertheless, parental distrust of vaccination, especially with regard to its safety and efficacy, hinders this process. Herein, we comprehensively summarize the available data on the safety and effectiveness of COVID-19 vaccine in children. The results show that the currently approved COVID-19 vaccine is safe and effective for children. Although two doses of vaccine in children seem insufficient to prevent Omicron infection, the booster dose provides enhanced protection against infection and severe illness. Most importantly, the bivalent vaccine has been approved for use in the pediatric population to extend the immune response to currently circulating Omicron variant. And the immune protection afforded to newborns after maternal vaccination appears to last only 6 months. Therefore, in the current situation where the rate of virus mutation is accelerating and the COVID-19 pandemic is still severe, it is crucial to extend vaccine protection to children over 6 months of age to weave a tighter safety net.
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COVID-19 , Niño , Recién Nacido , Adulto , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , SARS-CoV-2 , Pandemias , VacunaciónRESUMEN
Quantifying multiple biomarkers with high sensitivity in tiny biological samples is essential to meet the growing demand for point-of-care testing. This paper reports the development of a novel microfluidic device integrated with mass-producible micropillar array electrodes (µAEs) for multiple biomarker detections. The µAE are mass-fabricated by soft lithography and hot embossing technique. Pt-Pd bimetallic nanoclusters (BNC) are modified on the surface of µAEs by constant potential (CP)/multi-potential step (MPS) electrodeposition strategies to improve the electroanalytical performance. The experimental result displays that Pt-Pd BNC/µAEs have good sensitivity enhancement compared with bare planar electrodes and bare µAEs, the enhancement being 56.5 and 9.5 times respectively, from the results of the H2O2 detection. Furthermore, glucose, uric acid and sarcosine were used as model biomarkers to show the biosensing capability with high sensitivity. The linear range and LOD of the glucose, uric acid and sarcosine detection are 0.1 mM-12 mM, 10 µM-800 µM and 2.5 µM-100 µM, 58.5, 3.4 and 0.4 µM, respectively. In particular, biosensing chips show wide linear ranges covering required detection ranges of glucose, uric acid and sarcosine in human serum, indicating the developed device has great potential in self-health management and clinical requirements.
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Técnicas Biosensibles , Microfluídica , Humanos , Ácido Úrico , Peróxido de Hidrógeno , Sarcosina , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , Glucosa , Biomarcadores , ElectrodosRESUMEN
Clusteroluminescence (CL) and through-space interactions (TSIs) of non-conjugated molecules have drawn more attention due to their unique photophysical behaviors that are different from largely conjugated luminogens. However, achieving red and even near-infrared (NIR) emission from such systems is still challenging due to the intrinsic drawbacks of non-conjugated molecules and the lack of theories for structure-property relationships. In this work, six phenolic resins are designed and synthesized based on two molecule-engineering strategies: increasing the number of TSIs units and introducing electron-donating/-withdrawing groups. All phenolic resins are verified as luminogens with CL property (CLgens), and the first example of CLgens with NIR emission (maximum emission wavelength ≥680â nm) and high absolute quantum yield (47 %) is reported. Experiments and theoretical analysis reveal that two TSIs types, through-space locally excited state and through-space charge transfer state, play essential roles in achieving CL from these non-conjugated polymers, which could be manipulated via changing structural conformation and electron density or altering electron transition behaviors. This work not only provides an approach to manipulate TSIs and CL of non-conjugated polymers but also endows commercially available phenolic resins with high practical value as luminescence materials.
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Wood rot fungus Fulvifomes siamensis infects multiple urban tree species commonly planted in Singapore. A commercial e-nose (Cyranose 320) was used to differentiate some plant and fungi volatiles. The e-nose distinctly clustered the volatiles at 0.25 ppm, and this sensitivity was further increased to 0.05 ppm with the use of nitrogen gas to purge the system and set up the baseline. Nitrogen gas baseline resulted in a higher magnitude of sensor responses and a higher number of responsive sensors. The specificity of the e-nose for F. siamensis was demonstrated by distinctive clustering of its pure culture, fruiting bodies collected from different tree species, and in diseased tissues infected by F. siamensis with a 15-min incubation time. This good specificity was supported by the unique volatile profiles revealed by SPME GC-MS analysis, which also identified the signature volatile for F. siamensis-1,2,4,5-tetrachloro-3,6-dimethoxybenzene. In field conditions, the e-nose successfully identified F. siamensis fruiting bodies on different tree species. The findings of concentration-based clustering and host-tree-specific volatile profiles for fruiting bodies provide further insights into the complexity of volatile-based diagnosis that should be taken into consideration for future studies.
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Nariz Electrónica , Compuestos Orgánicos Volátiles , Hongos , Cromatografía de Gases y Espectrometría de Masas/métodos , Nitrógeno , Odorantes/análisis , Microextracción en Fase Sólida/métodos , Árboles , Compuestos Orgánicos Volátiles/análisis , Madera/química , Panadizo InterdigitalRESUMEN
AIMS: Recent studies have demonstrated the associations of the consumption of different beverages with cardiometabolic diseases, whereas no studies have investigated such associations in heart failure (HF). Thus, this study aimed to explore the associations of the consumption of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and pure fruit/vegetable juices (PJs) with the risk of incident HF. METHODS AND RESULTS: This prospective cohort study included 209 829 participants in the UK Biobank who completed at least one 24-h diet questionnaire and who were free of baseline HF. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 9.9 years, 4328 incident HF cases were recorded. Compared to corresponding non-consumers, individuals who consumed >2 L/week SSBs or ASBs had an increased risk of HF (HR: 1.22, 95% CI: 1.08-1.38 and HR: 1.30, 95% CI: 1.16-1.47, respectively) in the multivariate adjusted model. An inverse association was observed between the consumption of >0-1 L/week PJs and the risk of HF (HR, 0.90; 95% CI, 0.83-0.98). Additionally, a significant interaction was observed between PJ consumption and sleep duration on HF risk (P for interaction = 0.030). CONCLUSIONS: Increased consumption of SSBs or ASBs may be an independent risk factor for HF, whereas moderate intake of PJs may have a protective effect on HF.
High intake of sugar-sweetened or artificially sweetened beverages was associated with an increased risk of heart failure, and moderate intake of pure fruit/vegetable juices was inversely associated with incident heart failure. Consumption of artificially sweetened beverages is a risk factor for heart failure; thus, it may not be a safe alternative to sugar. Moderate consumption of pure fruit/vegetable juices may be a preventive strategy for heart failure.
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Insuficiencia Cardíaca , Bebidas Azucaradas , Humanos , Bebidas Azucaradas/efectos adversos , Edulcorantes/efectos adversos , Estudios Prospectivos , Bebidas/efectos adversos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiologíaRESUMEN
Autoimmune hepatitis (AIH) is a typical T cell-mediated chronic liver disease with a higher incidence in females. However, the molecular mechanism for the female predisposition is poorly understood. Estrogen sulfotransferase (Est) is a conjugating enzyme best known for its function in sulfonating and deactivating estrogens. The goal of this study is to investigate whether and how Est plays a role in the higher incidence of AIH in females. Concanavalin A (ConA) was used to induce T cell-mediated hepatitis in female mice. We first showed that Est was highly induced in the liver of ConA-treated mice. Systemic or hepatocyte-specific ablation of Est, or pharmacological inhibition of Est, protected female mice from ConA-induced hepatitis regardless of ovariectomy, suggesting the effect of Est inhibition was estrogen independent. In contrast, we found that hepatocyte-specific transgenic reconstitution of Est in the whole-body Est knockout (EstKO) mice abolished the protective phenotype. Upon the ConA challenge, EstKO mice exhibited a more robust inflammatory response with elevated production of proinflammatory cytokines and changed liver infiltration of immune cells. Mechanistically, we determined that ablation of Est led to the hepatic induction of lipocalin 2 (Lcn2), whereas ablation of Lcn2 abolished the protective phenotype of EstKO females. Our findings demonstrate that hepatocyte Est is required for the sensitivity of female mice to ConA-induced and T cell-mediated hepatitis in an estrogen-independent manner. Est ablation may have protected female mice from ConA-induced hepatitis by upregulating Lcn2. Pharmacological inhibition of Est might be a potential strategy for the treatment of AIH.
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Estrógenos , Hepatitis Autoinmune , Ratones , Femenino , Animales , Concanavalina A/toxicidad , Estrógenos/farmacología , Linfocitos T , Hepatocitos , Hígado , Hepatitis Autoinmune/genética , Hepatitis Autoinmune/prevención & control , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
Plasma cell-free DNA (cfDNA) are small molecules generated through a non-random fragmentation procedure. Despite commendable translational values in cancer liquid biopsy, however, the biology of cfDNA, especially the principles of cfDNA fragmentation, remains largely elusive. Through orientation-aware analyses of cfDNA fragmentation patterns against the nucleosome structure and integration with multidimensional functional genomics data, here we report a DNA methylation - nuclease preference - cutting end - size distribution axis, demonstrating the role of DNA methylation as a functional molecular regulator of cfDNA fragmentation. Hence, low-level DNA methylation could increase nucleosome accessibility and alter the cutting activities of nucleases during DNA fragmentation, which further leads to variation in cutting sites and size distribution of cfDNA. We further develop a cfDNA ending preference-based metric for cancer diagnosis, whose performance has been validated by multiple pan-cancer datasets. Our work sheds light on the molecular basis of cfDNA fragmentation towards broader applications in cancer liquid biopsy.
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Ácidos Nucleicos Libres de Células , Neoplasias , Humanos , Nucleosomas/genética , Metilación de ADN/genética , Fragmentación del ADN , Neoplasias/genética , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: Testosterone has an impact on metabolic disorders and men with type 2 diabetes mellitus (T2DM) are predisposed to hypogonadism; meanwhile, patients with T2DM have higher risk of NAFLD. Therefore, we speculate that testosterone may affect the progression of NAFLD in T2DM patients and we aim to investigate whether total testosterone is associated with NAFLD progression in men with T2DM. METHODS: A cross-sectional study. A total of 1782 male participants with T2DM were enrolled from seven communities in Shanghai. Probable nonalcoholic steatohepatitis (NASH) was defined by the concurrence of NAFLD and metabolic syndrome (MetS). NAFLD fibrosis score was used to identify patients with probable advanced fibrosis. Multinomial logistic regression and ordinal logistic regression was used to measure the association of total testosterone (independent variable) and the progression category of NAFLD (dependent variable). RESULTS: In male, TT quartiles were negatively associated with probable NASH (Q1 vs. Q4 OR 2.07 95% CI 1.31-3.28, P for trend = 0.001) and inflammatory progression of NAFLD with OR of 1 SD increment of ln (TT) 0.81 (95% CI 0.72-0.92, P for trend < 0.001), but positively with fibrotic progression (Q1 vs. Q4 OR 0.45, 95% CI 0.29-0.72, P for trend = 0.001) with OR of 1 SD increment of ln (TT) 1.24 (95% CI 1.07-1.45). According to stratified analyses, for inflammatory progression, the interactions of age strata, duration of diabetes strata, and dyslipidemia status with 1 SD increment of ln (TT) were significant (P for interaction 0.007, 0.003, and 0.012, respectively); as for fibrotic progression, we found no interactions (all P for interaction ≥ 0.05). CONCLUSIONS: Different associations between TT and inflammatory and fibrotic progression of NAFLD in male were observed, suggesting different roles of TT in inflammatory and fibrotic stages of NAFLD.
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Estudios Transversales , Testosterona , China , Cirrosis Hepática/complicacionesRESUMEN
Visual loop-mediated isothermal amplification (LAMP) is qualified to be applied in the field to detect pathogens due to its simplicity, rapidity and cost saving. However, the color changes in currently reported visual reverse transcription LAMP (RT-LAMP) for foot-and-mouth disease virus (FMDV) detection are not so obvious to the naked eye, so interpretation of results is troublesome. In this study, a new naked-eye visual RT-LAMP to detect all seven distinct serotypes of FMDV was established based on the 3D genes by using pH-sensitive neutral red as the indicator, rendering a sharp contrast of color changes between the negative (light orange) and the positive (pink). Analytical sensitivity tests showed that the detection limit of the visual RT-LAMP was 104 copies/µL while those were 103 and 104 copies/µL for the RT-qPCR and conventional RT-PCR methods, respectively. Specificity tests proved that the established visual RT-LAMP assay had no cross-reactivity with other common livestock viruses. Furthermore, the analysis of 59 clinical samples showed 98.31% and 100% concordance with the RT-qPCR and the RT-PCR, respectively. The pan-serotypic FMD visual RT-LAMP assay could be suitable for a pen-side test of all seven serotypes of FMDV because the results could be easily distinguished by the naked eye without the requirement of complicated instruments and professional technicians. Hence, the novel method may have a promising prospect in field tests which exert an important role in monitoring, preventing, and controlling FMD, especially in regions with no PCR or qPCR instrument available.